The goal is to examine the relationship between opioid binding sites in the CNS and the response to opioid and nonopioid drugs. Chronic opioid antagonist treatment has been demonstrated to produce a parallel increase in opioid receptors (upregulation) and the potency of opioid agonists (supersensitivity). The correlation between opioid binding site characteristics and pharmacodynamic effect provides a unique opportunity to study the mechanism of action of opioid analgesic drugs at the receptor level. An in depth understanding of the role that receptor regulation plays in opioid activity is important in understanding how analgesia, tolerance, dependence, as well as opioid toxic effects, are mediated, and may provide critical information for developing new strategies for pain relief. The studies in this project will examine upregulation and supersensitivity in parallel receptor and pharmacological studies. The modulation of binding sites in the CNS by chronic opioid antagonist treatment will be explored to determine the factors that regulate opioid receptor increases and the nature of the increases. The necessary conditions for producing upregulation will be examined and related to plasma and brain drug level required for receptor modification. Studies on the effect of upregulation on opioid tolerance and dependence will provide important information on the possible role of receptor modification in these phenomena. The effects of endocrine and drug factors and compounds that interfere with protein synthesis will help to reveal the mechanisms that mediate upregulation and supersensitivity. Opioid agonist effects will be studied to determine if chronic opioid antagonist treatment modifies antagonism of analgesic and toxic effects. In all of these studies, receptor changes will be interpreted in light of pharmacological changes so that binding studies can be linked to functional relevance. The studies proposed in this application take advantage of the reliable functional and biochemical effects of chronic opioid antagonist treatment to probe the mechanism of action of opioid drugs. Further, since opioid antagonist maintenance is a current treatment modality for opioid drug abuse, these studies may provide clinically relevant information on the consequences of chronic treatment. The studies outline in the proposal will provide both practical and conceptual information on the relationship between opioid receptors and pharmacodynamic effect.